ATM And DNA Damage Repair

Inbal Dar, Sharon Biton, Yosef Shiloh, and Ari Barzilai

Cellular DNA damage such as double-strand breaks sets off restorative signaling cascades. One of these molecules is the protein kinase ataxia-telangiectasia mutated (ATM). Interestingly, ATM mutations cause abnormalities affecting proliferating cells, including immunodeficiency and an increase in certain cancers, but also cerebellar degeneration. The mechanism of the loss of cerebellar granule cells and Purkinje cells, and thus the ataxia, is not obvious. This week, Dar et al. examined the activation and subcellular localization of ATM in mouse cerebellar neurons. An anti-ATM antibody revealed predominantly nuclear expression of ATM. DNA damage by ionizing radiation induced ATM autophosphorylation, colocalization with a marker of double-strand breaks, and phosphorylation of downstream targets of ATM. The evidence thus suggests that ATM is operating in cerebellar neurons in a fashion in a similar fashion to that in proliferating cells. Thus, failure of DNA repair likely underlies the loss of granule cells and Purkinje cells in ataxia-telangiectasia.

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